Cardiovascular & Haematological Disorders - Drug Targets - Volume 11, Issue 2, 2011

Aims: The absolute white blood cell (WBC) count and neutrophil to lymphocyte (N/L) ratio are predictors of death/myocardial infarction in patients who have undergone coronary angiography. We hypothesized that a pre-procedural elevated WBC count and an elevated N/L ratio would be a predictor of development of significant ventricular arrhythmias in subjects undergoing percutaneous coronary intervention (PCI). Methods and Results: We retrieved the data for all patients developing ventricular arrhythmia during PCI between 1999 to 2009 from our cath lab database (from 30,798 records), a total of 70 patients (Group I), and tabulated their WBC counts and absolute neutrophil and lymphocyte counts as well as N/L ratios. We compared the data with a random group of age, gender, medications and pre-existing condition matched controls (n=70) (Group II). We also adjusted for amount of myocardium under jeopardy. Group I had a significantly higher total WBC count (means 14,344 Vs 6852; 95% CI; p=0.0004); neutrophil count (means 75.79% Vs 58.06%; 95% CI; p<0.0001) and N/L ratio (means 3.79 Vs 1.56; 95% CI; p<0.0001) [means compared with t test]. Conclusion: Our data suggests a pre-procedural elevated WBC count, neutrophils and elevated N/L ratio are predictors of significant ventricular arrhythmias in patients undergoing percutaneous coronary intervention (PCI).

Myocardial fibrosis is commonly observed in left ventricular (LV) hypertrophied heart during Arterial Hypertension. This pathological change coupled with vascular stiffening with aging and diabetes may reduce the cardiovascular system elasticity contributing to the functional impairment. Both the LV adaptive response to the increasing blood pressure and the oxidative damage contribute to myocardial fibrosis; in particular, reactive oxygen species (ROS) induce the formation of reactive electrophilic carbonyl species by reacting with lipids and sugars which in turn react with proteins forming irreversible adducts (AGEs, ALEs and EAGLEs) and cross-links. The vascular wall matrix then becomes less distensible, as the formation of the adducts induces greater capacity in collagen to resist normal turnover. Therefore, monitoring cardiac fibrosis and markers of collagen synthesis, degradation and non-enzymatic cross-linking and the use of drugs that revert collagen accumulation and/or prevent/repair non-enzymatic cross-linking might represent a novel opportunity to alter the natural history of hypertensive heart disease. Recent evidences have suggested to target the excess of collagen cross-links; initial evidence seems to show that fibrosis is not affected to the same degree by all anti-hypertensive agents. ACEI and ARBs appear particularly effective. Finally, agents acting as cross-link breakers on AGEs or preventing AGEs formation or affecting the TTG activity are emerging.

Background: We decided to examine whether there are differences in the levels of lipopolysaccharide (LPS) in various groups of patients suffering from left ventricular dysfunction, requiring no intravenous therapy. Materials and methods: We studied 37 patients (ranging from 39 to 80 years, mean age of 59.8 years, SD 9.5) with left ventricular dysfunction caused by dilated cardiomyopathy, valvular heart disease or chronic ischemic cardiomyopathy. These patients were compared to 29 healthy subjects and 7 acute myocardial infarction (AMI) patients. The LPS levels were analyzed and correlated to the echocardiographic index of left ventricular impairment and to the clinical parameters. Results: The plasma levels of LPS were lower in patients with a chronic LV dysfunction than in the control group but without reaching any statistical significance (chronic LV dysfunction patients 6.33±5.03 pg/ml, AMI patients 13.58±19.14 pg/ml, healthy controls 11.12±12.97 pg/ml). The values observed in AMI patients were similar to those of the control group, without any significant differences. No significant correlation of the LPS levels was obseved either with the echocardiographic index of left ventricular impairment or with the clinical parameters. Conclusions: It is probable that LPS does not play any major role in the progression of LV dysfunction. The possible role of LPS in critical heart failure should therefore be better evaluated.

Dual anti-platelet therapy remains a cornerstone in the management of patients suffering from acute coronary syndromes (ACS). The combination of aspirin and clopidogrel has been shown to result in significant reductions in cardiovascular end points including recurrent infarction and death in several randomised control trial of patients with ACS. However, many patients still experience ischaemic events on the combination of aspirin and clopidogrel. Aspirin is a relatively weak anti platelet agent. Clopidogrel is a pro drug that required activation by hepatic metabolism and hence its onset of action is delayed; there is genetic variation in the clinical response to the drug, the platelet inhibition is irreversible and no intravenous form is available. Consequently new anti-platelet agents have been developed to address the short falls of this combination therapy. This paper discusses existing anti-platelet regimes and focuses on novel antiplatelet agents that are currently under clinical evaluation.

The synthesis and antihypertensive activity of a group of imidazo[1,2-a]pyridine is described. New synthesized compound have been tested both in vivo and in vitro as antagonists on Angiotensin AT1 receptor, and compared to Losartan, used as reference drug. Binding assay an Angiotensin AT1 receptor were carried on as well. Compounds 6b and 6g showed a potent antihypertensive activity and an high affinity on AT1 receptor.

Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to reduce reperfusion injury after coronary revascularization in acute myocardial infarction and severe coronary artery disease had been approved in animal studies and further demonstrated clinical benefits in phase II study: the COMMA trial and phase III study: the PRIMOCABG trial. However, the negative results of pexelizumab were observed in the COMPLY trial and the APEX-AMI trial. In the APEX-AMI trial, the effectiveness of pexelizumab has reasoned to be prominent in high-risk patients. Similarly, an exploratory analysis of the combined PRIMO-CABG I and II data set using an established predictive risk model demonstrated a mortality benefit for high-risk surgical patients. Accordingly, the result of these trials supported a moderational model to explain the usefulness of pexelizumab affected by the baseline risk profiles of patients. In this regard, we have commented that pexelizumab may be hazardous to patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention without using adequate anti-thrombotic agents (glycoprotein IIb-IIIa antiplatelet inhibitors, clopidogrel and haparin non-responders) according to the results of the experiment by professor Røger and coworkers and the mathematic estimations of the relative risks. Herein, we proposed a mediational model to account for the effectiveness of pexelizumab.

Mediastinal mass radiotherapy as adjuvant or primary treatment is usually performed for lung, breast and oesophagus cancer, for lymphoma and thymoma. However, untoward late cardiac and vascular adverse effects can develop that were underrecognized in the past because a very long latency from exposure to clinical manifestations is needed. Moreover, the true cumulative incidence of these complications is hard to correctly evaluate. Thoracic Radiotherapy (TR) may determine pathological involvement of pericardium, myocardium, cardiac valves, conduction system, coronary arteries and of subclavian and carotid arteries. The main clinical features of radiation induced cardiac and vascular diseases are discussed in the review. Recently, an increased risk of strokes and transient ischemic attacks (TIAs) has also been shown after TR, and the possible mechanisms as well as the measures useful in decreasing the risk are discussed. Other emerging aspects of radiation induced damages, just like malfunction of Pace Maker and of Implantable Defibrillators as well as malfunction of coronary bypass and coronary stents, probably will become more frequent in the next future. Finally, the current knowledge concerning the effects of the new modalities of administration of TR (doses, techniques) on the cardiovascular risk is reported, as well as the important clinical problem linked to the appropriate evaluation of the risk/benefit ratio of performing TR in different clinical situations.

The nitric oxide (NO) cascade and endothelial NO synthase (eNOS) are best known for their role in endothelium-mediated relaxation of vascular smooth muscle (VSM). NO generated by eNOS has been established as a key regulatory signaling molecule in the vasculature. The activities of eNOS are controlled by intracellular calcium/calmodulin (CaM) and by binding of the molecular chaperone heat-shock protein 90 (Hsp90). A number of studies have demonstrated a close association between insulin resistance (IR) and NO bioactivity. Some recent studies demonstrate that insulin signaling is essential for normal cardiovascular (CV) function and lack of it such as IR result in CV dysfunction and disease. A key step in the initiation and progression of atherosclerosis is a reduction in the bioactivity of endothelial cell-derived NO. Multiple changes in endothelial function and eNOS activity accompany the onset and development of Type 2 diabetes mellitus (T2DM) and contribute to the development of cardiovascular disease (CVD). This review focuses on recent findings about regulation of eNOS in pathophysiological conditions such are: IR, T2DM and CVD.

Among concepts proposed to elucidate atherosclerosis process, the oxidative modification hypothesis is more considered to be investigated in studies. Based on the hypothesis, the LDL components are chemically modified due to oxidative stress within subendothelial space of vessels. The cells are able to recognize the oxidized LDL (ox-LDL) preparations so that inflammatory events spread through intracellular pathways and lead to the cellular dysfunction and the production of atherosclerotic plaques. The circulating ox-LDL level is suggested as biomarker of atherogenic lesions. However, it is not confirmed in some studies since the circulating ox-LDL clearance during the extent of atherosclerosis process is related to function of scavenger receptors and the serum anti LDL levels. The report is focused on the biochemical characteristics of modified LDL components, the cellular internalization of ox-LDL particles through the scavenger receptors, prediction of consensus blocks in the receptor sequences and the circulating ox-LDL assessments in cardiovascular complications.